Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease

Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

Chlorogenic acid supported strontium polyphenol networks ensemble microneedle patch to promote diabetic wound healing

Delayed or non-healing of diabetic wounds is a significant complication,often attributed to high glucose-induced M1 macrophage accumulation,impaired angiogenesis,and reactive oxygen species(ROS)buildup.Addressing this,we introduced a strontium polyphenol network microneedle patch(SrC-MPNs@MN-PP)for percutaneous drug delivery.This patch,formulated with polymer poly(γ-glutamic acid)(γ-PGA)and epsilon-poly-l-lysine(ε-PLL),incorporates strontium polyphenol networks(SrC-MPNs).The release of chlorogenic acid(CGA)from SrC-MPNs not only neutralizes ROS,but strontium ions also foster angiogen-esis.Consequently,SrC-MPNs@MN-PP can ameliorate the diabetic wound microenvironment and expedite healing.

Intelligent microneedle patch with prolonged local release of hydrogen and magnesium ions for diabetic wound healing

Diabetes mellitus,an epidemic with a rapidly increasing number of patients,always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization,decreased angiogenesis and increased reactive oxygen species(ROS)in the microenvironment.Herein,a poly(lactic-co-glycolic acid)(PLGA)-based microneedle patch loaded with magnesium hydride(MgH_(2))(MN-MgH_(2))is manufactured for defeating diabetic wounds.The application of microneedle patch contributes to the transdermal delivery and the prolonged release of MgH_(2) that can generate hydrogen(H_(2))and magnesium ions(Mg^(2+))after reaction with body fluids.The released H_(2) reduces the production of ROS,transforming the pathological microenvironment induced by diabetes mellitus.Meanwhile,the released Mg^(2+)promotes the polarization of pro-healing M2 macrophages.Consequently,cell proliferation and migration are improved,and angiogenesis and tissue regeneration are enhanced.Such intelligent microneedle patch provides a novel way for accelerating wound healing through steadily preserving and releasing of H_(2) and Mg^(2+)locally and sustainably.

Rapidly separable bubble microneedle patch for effective local anesthesia

In cutaneous cosmetology surgery,local injection or coated anesthetics are generally used to provide analgesia at the treatment site to achieve painless operation.Due to the barrier of corneum,topical cream may cause uncertain dosage and delayed analgesia.Local injection has problems such as pain,infection,and misoperation.Therefore,it is necessary to develop a painless and rapid administration method for local anesthesia.Here,a lidocaine/hyaluronic acid bubble microneedle patch(Lido/HA bMNP)was prepared for rapid drug delivery and efficient analgesia.The bubble structure between microneedles(MNs)and the backing layer allowed the MNs to efficiently penetrate into the skin and remove from the backing layer under shear force to rapidly complete the administration.Drugs were quickly released with the dissolution of HA within 15 s,which immediately played an analgesic effect and lasted for 1 h.Lido/HA bMNP could deliver precise doses to the skin in an extremely short time,which had the advantages of convenient operation,high biosafety,rapid onset of analgesia,and reasonable pain relief time.This patch provided an alternative way for local anesthesia and it was a promising transdermal drug delivery method for the realization of high quality and efficiency“painless medical beauty”.

Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation

Delayed wound healing in diabetes is a global challenge,and the development of related drugs is a clinical problem to be solved.In this study,purpurolide C(PC),a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum,was found to promote diabetic wound healing.To investigate the key regulation targets of PC,in vitro RNA-seq,molecular docking calcula-tions,TLR4-MD2 dimerization SDS-PAGE detection,and surface plasmon resonance(SPR)were per-formed,indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation.Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing.Furthermore,a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC(PC@MLIP MN)was developed,which overcame the poor water solubility and weak skin permeability of PC,so that successfully punctured the skin and delivered PC to local tissues,and accurately regulated macrophage polarization in diabetic wound management.Overall,PC is an anti-inflammatory small molecule compound with a well-defined structure and dualtarget regulation,and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.